Prior work from our Emphysema/COPD Research Center (ECRC), in collaboration with colleagues at the[unreadable] University of British Columbia, Vancouver, has provided strong evidence that adaptive immune abnormalities[unreadable] play a critical role in the pathogenesis of peripheral airway remodeling in Chronic Obstructive Pulmonary[unreadable] Disease. We will outline our evidence from both lung tissue explants and peripheral blood markers that[unreadable] supports this hypothesis. We further hypothesize that modulation of these immune responses with specific[unreadable] biologic agents could ablate, or ameliorate these pathogenic mechanisms, and alter the natural history of[unreadable] COPD. This proposal outlines a prototype aerosol intervention protocol based upon the long-term experience[unreadable] at the University of Pittsburgh with the use of aerosol cyclosporine (aCsA) for the prevention of bronchiolar[unreadable] inflammation in the lung transplantation population.[unreadable] This project will outline sequential Phase I and Phase I/I I trials to explore the short (28 days) and[unreadable] intermediate term (6 month) safety of aCsA immunotherapy applied to a population of patients with[unreadable] moderately severe (Gold III) COPD. A Phase I initial dose escalation-deescalation protocol (DEP) will[unreadable] examine short-term safety issues with attention to airway reactivity and infection risk. The observations[unreadable] learned from the DEP, will be incorporated into the design and execution of a randomized, parallel-design,[unreadable] moderate duration Phase I/I I exploratory trial. Our therapeutic goal in both the DEP and AIC will be to define[unreadable] the minimum tolerated aCsA dose associated with biologic efficacy, using peripheral blood marker[unreadable] bioassays.[unreadable] The data and human specimens from this intervention trial will be used collaboratively with Projects 1-3 of[unreadable] this proposal to gain insight into the pathogenesis of moderately advanced COPD under the influence of[unreadable] immunoregulatory control.[unreadable] We believe aCsA provides an immediately available, innovative, approach to potentially treat the adaptive[unreadable] immune response documented in COPD patients. The clinical investigation protocol outlined in this proposal[unreadable] will fulfill the stated application goal to identify, " high-risk/high-gain tests of novel therapeutic approaches,[unreadable] both in animal models and as Phase l/ll clinical trials."